The present invention is in the field of identification of disease states by measuring levels of biomarkers that are associated with the disease state.
The complex networks of biochemical processes that underlie living systems are amenable to analysis to determine the state of the living system. For example, under a pathological challenge, there is a shift in these networks as the pathogen affects the system and the system responds to the challenge. For example, various genes involved in different disease processes have been studied and modeled in an attempt to further understand drivers of complex disease states (see, e.g., U.S. Pub. No. 20060241869). As underlying biochemical processes change, there is an attendant change in biological substances that are consumed or produced as the system is challenged. Depending on the specific type of challenge, including bacterial versus viral and different bacterial strains, the levels of different biological substances change. Biological substances that change depending on the pathological condition or “disease state” are referred to as “biomarkers.” The invention relies on measuring one or more biomarkers associated with the disease state from a biological sample in order to assess the subject's disease state and specifically address the need in the art for fast and reliable assays of disease states in order to prevent, treat or eliminate infection. Developing a refined biomarker phase portrait platform is useful for early diagnosis of complex diseases with high specificity and sensitivity.
Biomarkers are potential tools for assessing disease state and associated therapeutic decision-making on a patient-by-patient basis. Due to the enormous network complexity underlying biological processes, there is a need in the art for understanding biomarker profiles or fingerprints associated for a specific disease. Without this basic understanding, the vast number of potential biomarkers associated with a disease can overwhelm the ability to rapidly and efficiently determine disease state. There are growing concerns that the rising expenditures in pharmaceutical research and development are not sustainable if sufficient gains for industry or society at large are not realized. Thus, there is a need for development of bioinformatics and associated methods that go beyond the mere collection of massive amount of data. Instead, there needs to be a focused effort on how biomarkers, personalized medicine, and the industry can successfully interact to create feasible clinical solutions. The methods and associated kits presented herein rely on parameterized biochemical pathway models reconstructed from the combination of collected data to provide a richer context in which to interpret associations between metabolite patterns and early disease onset, facilitating more robust points for therapeutic intervention.
Cachexia is a physical condition characterized by weight loss, body wasting and anorexia associated with the host immune response. Cachexia is commonly associated with any one or more underlying disorders such as cancer, infectious disease (AIDs, tuberculosis), and certain autoimmune disorders. Cachexia is a particularly useful pathological condition to model because its underlying biochemical pathways and associated biomarkers have been well-studied (Butz et al. (2006)). Cachexia is readily induced experimentally in animals by injection of bacterial lipopolysaccaride (LPS). The disease is known to be catabolic to muscle tissue and depresses growth via immune stimulation. The basic platform technology of utilizing biomarker profiles as a function of disease state in an assay for assessing disease state in a subject is demonstrated for cachexia.
Immune response to endotoxin has been studied (e.g., Krabbe et al., Clinic. Diag. Lab. Immun. (2001) 8: 333-338). For example, Krabbe et al. shows the change in body temperature, TNF-α, sTNFR-I, circulating monocytes and a variety of interleukin family members after endotoxin administration. Waters et al. (Chem. Res. Toxicol. 2005) discloses NMR-detected changes for a number of substances in urine, blood plasma, renal cortex, and liver in rats following thioacetamide treatment. Those studies, however, do not provide comprehensive information about biomarker profile changes as a function of disease progression, ranging from onset to recovery, required in a commercially-feasible assay of cachexia and related catabolic diseases.
The biomarker profile analysis of the present invention is capable of providing information not currently available in other assays known in the art. For example, because viruses and bacterium have unique effects on certain biochemical pathways, assays relying on measured biomarker profiles provide the ability to distinguish between bacterial and viral infections. This is an important aspect and is needed in the art in combination with rapid and reliable assays order to prevent unnecessary antibiotic use (and attendant bacterial resistance development) for situations where the disease state has a viral origin.